Abstract
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
MeSH terms
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Adenosine Triphosphate / chemistry
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Binding Sites
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Chemistry, Pharmaceutical / methods*
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrogen Bonding
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Inhibitory Concentration 50
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Models, Chemical
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Benzimidazoles
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Enzyme Inhibitors
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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Protein-Tyrosine Kinases
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emt protein-tyrosine kinase